The use of various porphyrin compounds in combination with irradiation--be the radiation visible or ionizing--in the treatment of diseased tissues is known. These treatments are often tumor-selective in that many porphyrin compounds accumulate at higher concentrations in tumor tissue than in normal tissue.
Porphyrin derivatives have been used in the treatment of tumors using the process of photodynamic therapy (PDT). In general, the PDT procedure involves administration of a sensitizer compound, such as the porphyrin derivatives, to target tissue and the subsequent treatment using light to that tissue. The PDT procedures function selectively to eradicate diseased tissue in the immediate area of the light source by generating singlet oxygen and activated molecules which damage tissue in that immediate area. Selectivity is attained through the preferential retention of the photosensitizer in rapidly metabolizing tissue such as tumors (Kessel, David, "Tumor Localization and Photosensitization by Derivatives of Hematoporphyrin. A Review" IEEE J. QUANTUM ELECTRON., QE 23(10): 1718-20 (1987)), virally infected cells (J. Chapman et al, "Inactivation of Viruses in Red Cell Concentrates with the Photo Sensitizer Benzoporphyrin Derivative (BPD)", TRANSFUSION 31(suppl): 47S Abstract S172, (1991) and J. North et al., "Viral Inactivation in Blood and Red Cell Concentrates with Benzoporphyrin Derivative", Blood Cells, 18: 129-140 (1992)), leukaemic cells (C. H. Jamieson, "Preferential Uptake of Benzoporphyrin Derivative by Leukaemic versus Normal Cells", Leuk. Res. (England) 1990, 14 (3), pp 209-210), psoriatic plaque (M. W. Rerns et al, "Response of Psoriasis to Red Laser Light (630 nm) Following Systemic Injection of Hematoporphyrin Derivative", Lasers Surg Med. 1984, 4(1) pp73-77), and atherosclerotic plaque (S. Andersson-Engels et al, "Fluorescence Diagnosis and Photochemical Treatment of Diseased Tissue Using Lasers: Part II", Anal. Chem. 62(1), 19A-27A (1990). The activation of the photosensitizer by visible light occurs only at the site at which visible light is present. Obviously, the photo-sensitizer-mediated destruction of tissue occurs only at the desired treatment site. The inactivated photosensitizer is nontoxic and will eventually be cleared from the body.
In a typical PDT treatment, PHOTOFRIN.RTM. porfimer sodium, BPD, or BPD-MA is injected into a patient. See, for instance, Ho et al., "Activity and Physicochemical Properties of PHOTOFRIN.RTM.", Photochemistry and Photobiology, 54(1), pp83-87 (1991); U.S. Pat. No. 4,866,168, to Dougherty et al. An appropriate dose is, e.g., 0.25-2.5 mg/kg of body weight, depending upon the diseased tissue and the choice of photosensitizer. At an appropriate time after photosensitizer administration, the diseased tissue or site is illuminated with a light source at an appropriate wavelength (630 nm for PHOTOFRIN.RTM. and 690 nm for BPD) to activate the photosensitizer. The thus-activated drug induces the formation of singlet oxygen and free radicals which damage the surrounding tissue. Both the diseased tissue and the vasculature feeding it are affected and the unwanted tissue is either directly destroyed or starved of oxygen and nutrients due to the occlusion of blood vessels. After the completion of the PDT, the treated tissue becomes necrotic and will either debride naturally or be debrided by the clinician.
Hematoporphyrin and PHOTOFRIN.RTM. have absorption spectra in the neighborhood of 630 nm. The absorption spectra of much blood and tissue is also in the same general spectral region. Consequently, much of the energy impinging upon the treated tissue is absorbed in the tissue itself, thereby limiting, in a practical sense, the physical depth to which the PDT treatment using hematoporphyrin and PHOTOFRIN.RTM. may be used. BPD-MA has an absorption spectra with peaks in longer wavelength regions, e.g., 690 nm. These compounds are viewed as improvements to the PDT treatment method in that the tissues do not absorb so much of the light energy and therefore allow increased depth of light penetration.
Nevertheless, PDT treatment for bulky or deep tumors, or for widespread disease, is limited by the depth of light penetration to only a few centimeters. Use of the ionizing radiation required by the instant invention will allow treatment of diseased or unwanted tissue at a depth much greater than with the PDT procedures.
An additional benefit to the procedure of this invention is that the benzoporphyrin derivative compounds leave the body much more quickly than the hematoporphyrin and PHOTOFRIN.RTM. materials. BPD leaves the body within a few days; the hematoporphyrin and PHOTOFRIN.RTM. materials may remain for weeks, leaving the patient's skin prone to sunburn in the interim.
The substitution of gamma radiation or x-rays for light in PDT has been investigated, with mixed results. Sometimes the porphyrin appears to protect the cells from radiation, sometimes sensitize those cells, and sometimes the compounds do nothing at all.
Mack et al., Cancer (1957) 29: 529-39 shows improved radiation tolerance in patients injected with hematoporphyrin prior to radiation therapy, but no extension of life over radiation-treated alone patients.
Novosel'tseva et al., Radiobiologiia (1979) 19(2): 297-301, tested the radioprotective effects of synthetic porphyrins.
However, Cohen et al., Cancer Research (1966) 26 Part 1: 1769-1773, reports that hematoporphyrin increased the sensitivity of rhabdomyosarcoma in mice to X-radiation. Hematoporphyrin complexed with copper exhibited no such enhancement.
Schwartz et al., Diagnosis and Therapy of Porphyrins and Lead Intoxication (1976) pp 229-31, shows the use of copper hematoporphyrin as a radiation sensitizer in the treatment of Katsumi dog tumors and various human tumors.
Kostron et al., Cancer, 5: 964-970 and Kostron et al., Jour. of Neuro-Onc. (1988) 6: 185-191, both discuss the effects of hematoporphyrin derivatives on rat gloime models in combination with stimulation by light and cobalt 60 or by a combination of the two. The use of radiation prior to administration of the porphyritic materials was not disclosed.
O'Hara et al., Int. J. Radiation Oncology Biol. Phys. (1989) 16: 1049-1052, discussed the effect of a group of water soluble, meso-substituted metalloporphyrins in combination with ionizing radiation on various tumor tissues.
A contrary teaching is found in Bellnier et al., Int. J. Rad. Biol. (1986) 50: 659-664. That document shows evidence that the mechanism of gamma-radiation and HPD photosensitization did not interact and that HPD did not augment the effects of x-radiation.
Also, Fiel et al., Res. Comm. Chem. Path. and Pharm. (1975) 10(1): 65-76, found that metal chelates of a mesoporphyrin in a lymphoid cell line were partially effective when added after irradiation as compared to pre-irradiation.